rs32209

chr5-128286799-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):c.6931A>G(p.Met2311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,694 control chromosomes in the GnomAD database, including 12,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2077 hom., cov: 33)
  • Exomes 𝑓: 0.071 (10631 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.82

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=1.4686584E-4).
• BP6: Variant 5-128286799-T-C is Benign according to our data. Variant chr5-128286799-T-C is described in ClinVar as [Benign]. Clinvar id is 129046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128286799-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6931A>G	p.Met2311Val	missense_variant	55/65	ENST00000262464.9
FBN2	XM_017009228.3	c.6778A>G	p.Met2260Val	missense_variant	54/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6931A>G	p.Met2311Val	missense_variant	55/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3715A>G		non_coding_transcript_exon_variant	30/38

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17723 AN: 152100 Hom.: 2074 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0875

GnomAD3 exomes AF: 0.112 AC: 28018 AN: 251276 Hom.: 4642 AF XY: 0.109 AC XY: 14771 AN XY: 135792

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0409

Gnomad ASJ exome AF: 0.0564

Gnomad EAS exome AF: 0.630

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0722

GnomAD4 exome AF: 0.0707 AC: 103374 AN: 1461476 Hom.: 10631 Cov.: 32 AF XY: 0.0718 AC XY: 52216 AN XY: 727074

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.0418

Gnomad4 ASJ exome AF: 0.0579

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.0514

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0839

GnomAD4 genome AF: 0.117 AC: 17748 AN: 152218 Hom.: 2077 Cov.: 33 AF XY: 0.121 AC XY: 9022 AN XY: 74416

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.0671

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.602

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0899

Alfa AF: 0.0618 Hom.: 1649

Bravo AF: 0.122

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.207 AC: 914

ESP6500EA AF: 0.0416 AC: 358

ExAC AF: 0.115 AC: 13976

Asia WGS AF: 0.313 AC: 1088 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Met2311Val in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 20.7% (914/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs32209). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.6931A>G (p.Met2311Val) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.1151322 (13966/121304 control chromosomes [2250 homozygotes]), which is approximately 92106 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T;.;.
MetaRNN	Benign	0.00015	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.70	N;.;N
MutationTaster	Benign	0.10	P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.45	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.43	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.13
MPC		0.24
ClinPred		0.017	T
GERP RS		5.3
Varity_R		0.085
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs32209; hg19: chr5-127622491; COSMIC: COSV52510041;